Endocrine III - diabetes Flashcards
What are the areas and cells in the pancreas that secrete substances - and which substances?
Islets of Langerhans
A cell: Glucagon
B cell: Insulin
D cell: Somatostatin
F cell: pancreatic polypeptide
What is the structure of insulin?
- Three disulphide bonds
- Two disulfide bonds connect chain A and B
- Third disulfide bond is an intrachain bond in chain A
How is insulin synthesised?
Transcription and translation of gene and mRNA forms preproinsulin -> forms proinsulin, ammonia group and signal sequence in the endoplasmic reticulum
Proinsulin forms insulin and C-peptide in the golgi apparatus
Insulin and C-peptide stored in granules, to be secreted by exocytosis
How does high glucose lead to insulin release?
1) B cells take up glucose by GLUT2, and glucokinase forms glucose 6-P which is used in oxidative metabolism for ATP formation
2) Blood glucose >5mM produce high ATP -> leads to closing of ATP-sensitive K+ channels
3) Membrane depolarisation results in calcium influx via VG calcium channel
4) High intracellular Ca triggers release of granules of insulin and C-peptide
What are the effects of insulin on adipose, striated muscle and liver?
Adipose tissue:
- Increased glucose uptake
- Increased lipogenesis
- Decreased lipolysis
Striated muscle:
- Increased glucose uptake
- Increased glycogen synthesis
- Increased protein synthesis
Liver:
- Decreased gluconeogenesis
- Increased glycogen synthesis
- Increased lipogenesis
What are the stimulating factors for insulin release from B cells?
- Elevated blood glucose - major activator
Enhancement of glucose-induced insulin release:
> Amino acids: arginine, leucine and glutamate
> Gut hormones: incretins
> Neural input: parasympathetic stimulation after a meal - ACh
What inhibits insulin secretion from B cells?
Epinephrine and norepinephrine
What happens once insulin binds to IRs?
Activates MAP kinase signalling pathway > cell growth, proliferation, gene expression
Also
Activates PI-3K signalling pathway >
- synthesis of lipids protein and glycogen ,
- cell survival and proliferation , and
- fusing of GLUT4 vesicles with cell surface membrane
What is the fasted state?
- Limited glucose availability
- Constant supply from the liver
- Other tissues switch to alternative fuels: FFA, ketones
What is the fed state?
- Glucose abundant
- Hepatic glucose production no longer required
- Alternative fuels not required
- Excess glucose diverted to energy storage
What is diabetes mellitus?
Deficient secretion or action of insulin
Two types
What is type 1 vs type 2 DM?
Type 1: atrophy or destruction of b cells of pancreas due to an immune response or viral infection
Type 2: insulin resistance - more insulin than normal is needed for the insulin receptors to repsond > b cell failure
What other forms of DM?
Maturity-onset diabetes of the young
Secondary diabetes
Gestational DM
Type 1 DM
Cause, signs, onset, complications, treatment
Autoimmune destruction of B cells
Very low or absent levels of insulin, very low C-peptide
Starts in childhood/adolescence
Osmolar symptoms
Complication: DKA
Treatment: lifelong insulin
Type 2 DM
Risk factors
Onset
Cause
Treatment
Risk factors: obesity, sedentary lifestyle, strong familial tendency, ageing
Gradual onset
Target tissues have insulin resistance, and decreased insulin secretion
Treatment: lifestyle > medications > insulins
What are the symptoms of DM?
Classic triad: 3 P’s - Polyphagia, polydipsia, polyuria
-Extreme fatigue
- Blurry vision
- Repeated infection
- Slow wound healing
- Weight loss
- Numbness in hands and feet
What are microvascular complications of DM?
Eye: damage blood vessels in eye > retinopathy, cataracts, glaucoma
Kidney: damage of small vessels > nephropathy
Neuropathy: damages peripheral nerves > pain/numbness. Feet wounds undetected > infected
What are the macrovascular complications of DM?
Brain: increased risk of stroke, cerebrovascular disease e.g. ischaemic attack
Heart: increased risk of CHD
Extremities: peripheral vascular disease reduced blood flow to legs > gangrene
What is required to diagnose diabetes?
- Fasting plasma glucose - 8 hours after meal
- Random plasma glucose
- Elevated HbA1c levels
- OGTT (gold standard)
- 2 hour plasma glucose - after glucose dose
What is HbA1c and its significance to DM?
Non-enzymatic glycation of haemoglobin
Indicator of long term glucose control over last 2-3 months
Poor glucose control, higher risk of complications
Used to diagnose DM
What is glucagon, how is it synthesised?
Peptide hormone with 29 amino acids in single pp chain
Proglucagon is a tissue specifically modified precursor
In A-cells proglucagon converted to glucagon by selective proteolytic cleavages in secretory granules
What are stimulating factors for glucagon secretion from a-cells
- Low blood glucose level - major activator
Enhancement of release: - Amino acids: arginine and alanine
- Stress hormones: epinephrine and norepinephrine
- Neural input: sympathetic stimulation during stress
What are inhibiting factors for glucagon secretion from a-cells?
Glucose
Insulin
How does glucagon bind to receptors and what does this cause?
- Glucagon binds to specific high-affinity G protein-coupled receptor (GPCR) on plasma membrane > activates adenylyl cyclase
- The formed cAMP binds to 2 regulatory subunits of cAMP-dependent protein kinase (PKA)
- Separates subunits and activates protein kinase A (PKA) > phosphorylates target enzymes using C-subunit
What are the actions of glucagon in the liver?
Liver:
- Activation of glycogenolysis and inhibition of glycogen synthesis
- Activation of gluconeogenesis and inhibition of glycolysis
- Activation of synthesis of fatty acids and cholesterol
What are the actions of glucagon in the renal cortex and fat cells?
Renal cortex:
- Gluconeogenesis and inhibition of glycolysis
Fat cells:
- Activation of TAG degradation
